Complexity and Heterogeneity of Alzheimer Disease Patients with Alzheimer disease progress in a stereotypical fashion, starting with neurofibrillary tangles (NFTs) in the medial temporal lobes and mild memory deficits, and progressing to lesions throughout the cortex, and marked dementia. While the pattern of progression is frequently similar, the pace at which this occurs varies dramatically among patients, for unknown reasons. The spread of tau containing tangles through the cortex seems to be due, at least in part, to propagation of misfolded tau molecules across neural circuits, in a manner analogous to prion induced templated misfolding disorders. We hypothesized that patient specific differences in tau seeded templated misfolding properties might underlie differences in propagation and rate of tangle formation as well as rate of clinical progression. Similar to prion ?strains? this would imply a different biology and biochemistry to tau proteins in different individuals. In this patient based study, we find that tau seeding activity, assessed with a TauRD FRET biosensor, does indeed vary dramatically among patients with AD. More aggressive tau seeding correlates with both an increase in the number of NFTs and with the rate of clinical deterioration. The seed competent tau from different cases have very different epitope maps, suggesting different conformations. In accord with the idea that tau varies among individuals, tau from different AD cases shows differential susceptibility to protease digestion, and different properties on size exclusion chromatography. One implication of these observations is that, at least for some anti-tau reagents being developed for therapeutics, one size might not fit all. These preliminary data support the idea that different tau strains exist even within what would conventionally be viewed as sporadic Alzheimer disease patients. This application will directly test a series of hypotheses that follow from these observations. Aim 1 tests the hypothesis that different tau strains occur in the brains of different individuals with Alzheimer disease. Aim 2 will use newly developed super-resolution microscopy methods (STORM) to test the hypothesis that more aggressive seeding properties are linked to more aggressive neurodegenerative phenotype, especially in terms of synaptotoxicity. Aim 3 examines the possibility that tau seeding can be detected in CSF of living patients, opening the opportunity to examine tau strain properties in life, potentially impacting patient care, the design of clinical trials, and providing a ?personalized medicine? approach. Together this application tests a fundamental question about Alzheimer disease ? is the heterogeneity that distinguishes one Alzheimer patient from another simply clinical chance, or is it due to an underlying difference in tau pathobiology?